Opioid antagonists are drugs which bind to the opioid receptors with higher affinity than opioid agonists but do not activate the opioid receptors. Commonly known opioid antagonists include drugs such as, for example, naltrexone, naloxone, nelmefene, nalorphine, and nalbuphine. Opioid antagonists effectively block the receptor from the action of both naturally occurring agonists (e.g., morphine, codeine, thebaine) and synthetic agonists (e.g., fentanyl, pethidine, levorphanol, methadone, tramadol, dextropropoxyphene) and uses include counteracting life-threatening depression of the central nervous and respiratory systems and thus are used for emergency overdose and dependence treatment (e.g., naloxone). There are many excellent reviews dedicated to different aspects of opioid antagonists [28-46].
Opioid receptor antagonists are known to modulate numerous central and peripheral effects including those associated with opioid abuse, the development of opioid tolerance and dependence, opioid-induced constipation, alcohol and cocaine abuse, depression, and immune responses [1]. The diverse therapeutic applications of μ-opioid antagonists include opioid-overdose-induced respiratory depression, opioid and cocaine abuse, alcohol dependence, smoking cessation, obesity, psychosis[1-19] and for the treatment of dyskinesia associated with Parkinson's disease [20-27].
The few opioid antagonists, currently on the market are represented by very few drugs (e.g., naloxone, naltrexone, and nalorphine (a partial agonist)) that have been shown to have therapeutic utility in a variety of indications. During last two decades only Alvimopan [13,14]—a peripherally acting μ-opioid antagonist for the treatment of postoperative ileus—has received approval as new drug. In addition, some azabicyclohexane derivatives and series of bi(hetero)aryl ethers as biological tools have been proposed as new chemical entities in this class of compounds [15].
Every chemical class of compounds with opioid-agonist activity has a structurally similar opioid-antagonist pair. Agonist-antagonist transformation in any of these cases takes place as a result of a small change in the structure of the agonist. The only exceptions, where the corresponding change for agonist-antagonist transformations has not been found, are the compounds of the fentanyl series.
Since the discovery of the “army” of opioid agonists of the fentanyl series (sufentanyl, alfentanyl, carfentanyl, remifentanyl, etc.) beginning in the 1960s, a structurally corresponding antagonist has not been found for any of these compounds. Thus, for decades there has been an evident gap in the art with respect to a possible specific structural change that could make possible the transformation of powerful opioid agonist properties of compounds of fentanyl series into powerful antagonists.
Similar to the general action of the opioid antagonists, antagonists of the adrenoreceptors (adrenergic receptors) bind to the adrenoreceptors and act to inhibit the action of those receptors. Alpha antagonists, or alpha-blockers, may selectively act at the α1-adrenoreceptors or at the α2-adrenoreceptors, or they may non-selectively act at both receptors. Commonly known α-blockers include, for example, phenoxybenzamine and phentolamine (non-selective); alfuzosin and prazosin (α1-blockers); and atipamezole, idazoxan, mirtazapine and yohimbine (α2-blockers). Generally, α-blockers have shown to be effective in the treatment of various medical conditions, including Raynaud's disease, hypertension, scleroderma, anxiety and panic disorders, and in the treatment of dyskinesia associated with Parkinson's disease.